Metastatic pancreatic cancer is a lethal disease. The genetic and epigenetic alterations and consequent changes in molecular signaling behind pancreatic cancer development and progression remain unclear. Our recent studies have shown that FoxM1 protein expression is drastically increased in primary pancreatic cancers when compared with that in normal pancreatic tissue. Consistently, human pancreatic cancer cells exhibit a substantial increase in FoxM1 expression. The levels of FoxM1 expression in pancreatic cancer cells directly correlate with metastatic potential. Genetically engineered overexpression of FoxM1 promotes the growth and metastasis of human pancreatic cancer in xenograft models, while FoxM1 knockdown does the opposite. Importantly, specific ablation of KLF4 in the pancreas of mice results in FoxM1 overexpression. Drastic FoxM1 overexpression and KLF4 underexpression are evident in pancreatic tumors developed in L-KrasG12D/+;pdx1-cre+ mice. We postulate that genetic and epigenetic changes of tumor suppressors and oncogenes and consequent alterations of FoxM1 signaling critically impact pancreatic cancer development and progression. To test our hypothesis, we propose the following three specific aims: 1. Determine the causal role of FoxM1 signaling in pancreatic cancer development and progression using genetically engineered mouse models. We will test our hypothesis that overexpression of FoxM1 is a critical event in activated Kras-mediated pancreatic carcinogenesis;thus genetic reduction or deletion FoxM1 will attenuate K-ras-mediated pancreatic carcinogenesis. 2. Determine the casual cooperation of loss of KLF4 and activation of Kras oncogene in pancreatic cancer development and progression. We will test our hypothesis that delayed onset or absence of invasive cancer in KLF4-null or activated Kras mouse models may require acquisition of additional genetic and/or epigenetic alterations and that a loss of KLF4 may cooperate with an activation of Kras;thus reduction or deletion of KLF4 in mouse should promote Kras-mediated pancreatic carcinogenesis. 3. Determine the mechanistic relationship between loss of KLF4 function and dysregulated FoxM1 expression and function in pancreatic epithelial cells. We will test our hypothesis that KLF4 transcriptionally represses the expression of FoxM1;loss of KLF4 during carcinogenesis of pancreas leads to overexpression of FoxM1;thus genetic deletion of FoxM1 will reverse the premalignant and malignant phenotypes of pancreas in KLF4-null mouse. These three specific aims are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. We predict that completion of these studies will provide insightful information for the molecular and genetic basis of pancreatic cancer pathogenesis and for identification of molecular targets to design effective preventive and therapeutic strategies. In the long term, our study also can lead to further investigation of the molecular mechanisms mediating disregulated FoxM1 signaling and its crosstalk with ras and KLF4 pathways. PUBLIC HEALTH RELEVANCE: Overexpression of FoxM1 is associated with tumorigenesis, while little is known for the causal mechanisms underlying dysregulated FoxM1 signaling and its impact on pancreatic cancer progression.